Scientists at Gladstone Institutes have made a groundbreaking discovery in the study of the human immune system. Using the next-generation CRISPR tool called base editing, they have created a detailed molecular map of how T cells—a type of immune cell—function in the body. This research, published in the journal Nature, provides valuable insights that could help improve existing immunotherapies and identify new targets for diseases like autoimmune disorders and cancer.
Led by Dr. Alex Marson, a senior investigator at Gladstone Institutes, the team delved into the DNA of T cells, examining specific nucleotides—the building blocks of genetic information—influencing how these immune cells respond to stimuli. They analyzed over 100,000 sites across nearly 400 genes found in functioning human T cells.
By pinpointing these crucial nucleotides, which serve as the genetic code for protein construction, scientists now have a clearer understanding of the locations within proteins that regulate immune responses essential for maintaining good health. These findings identify potential sites that can be targeted with future drugs designed to modulate the immune system.
Dr. Marson expresses his excitement about the precision and breadth of the team’s discoveries, stating that they have created highly informative maps of DNA sequences and protein sites that directly influence human immune responses. He also emphasizes that these mappings are critical for understanding mutations observed in patients with immune disorders. Moreover, the vast genetic dataset obtained from this study also serves as a valuable resource, providing vital information for developing immunotherapies to combat cancer, autoimmune diseases, infectious diseases, and more.
T cells play a central role in immune responses and regulation, making them a significant focus for scientists studying complex diseases such as cancer and immune disorders. Over the past decade, researchers, including those in the Marson lab, have used the gene-editing technology CRISPR to investigate the mechanisms of primary immune cells.
In this study, the team took their research a step further by leveraging base editing, a newer form of CRISPR technology, to make more targeted alterations to hundreds or thousands of DNA sites within individual genes, enabling them to obtain a more intricate and detailed understanding of these genes.
By working with primary T cells obtained from human blood donors, the results of this study have high clinical relevance. Dr. Ralf Schmidt, co-first author of the paper and a medical fellow at the Medical University of Vienna, emphasizes that the study delves into the genetic basis of immune cell functions. The ability to investigate T cells at the nucleotide level provides blueprints for drug development, diagnostic tools, and other scientific endeavors.
Given the large amount of data generated from analyzing over 100,000 sites on T cells, computational genomics played a crucial role in this study. Dr. Carl Ward, a postdoctoral researcher at Gladstone Institutes and co-first author, led the team’s efforts in this area. By focusing on important measures of cell function, Ward hopes that the data can become an invaluable resource for both immunologists and drug developers.
The ability to assign specific functions to previously mysterious mutations is a significant breakthrough highlighted by Ward. The detailed functional maps created in this study can also be combined with existing datasets and artificial intelligence tools to enhance discoveries and predict new avenues for research.
Ward believes that this Nature study marks only the beginning of a new era in understanding immune cell function. He anticipates that our ability to treat diseases will continue to improve as we gain a deeper understanding of these maps. This knowledge can be used to design therapies that enhance T cell function for cancer treatments or suppress it for the treatment of autoimmune diseases.
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